Human Growth Hormone (hGH) Human Growth Hormone (hGH) ¢â‚¬¢hGH consists of...

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Transcript of Human Growth Hormone (hGH) Human Growth Hormone (hGH) ¢â‚¬¢hGH consists of...

  • Human Growth Hormone (hGH)

    • hGH consists of a single polypeptide chain of 191 a.a residues and two disulphide bridge

    • hGH , Prl and hPL have 85 % a.a similarity • The hGH gene is located in chromosome 17

    q 22-24

    • hGH-1 gene is solely responsible for coding pituitary GH

    • hGH constitute 4 -10 % of the net pituitary gland weight

  • Structure of GH

  • GH SECRETION

    • GH secretion is pulsetile (8 pulses / day)

    • 50 % of pulses happen during early nighttime hours (follow onset of deep sleep)

    • Suppressed by hyperglycemia, obesity, hypothyroidism and excess glucocorticoid

    • Acts directly on growth plate and through IGF1(endocrine and autocrine actions)

    • IGF II is main mediator of intrauterine growth and is not regulated by GH secretion

  • Push –Pull system for GH secretion

  • GH SECRETION

    Stimulatory hypothalamic factors

    • Deep sleep

    •  -adrenergic stimulation

    • Sex steroid (Testosterone, E2)

    • Stress (Exercise, fasting, emotional)

    •  Amino acid,  Glucose,  FFA

  • GH SECRETION

    Stimulatory Neurotransmitters

    • Dopaminergic (L- Dopa)

    • Adrenergic (-agonist = Clonidine,

    -antagonist = Propranolol)

    • Serotonorgic (5-hydroxytryptamine)

    • Catecholaminergic (Methylcholine)

    • Histaminergic

    • GABA-ergic (Valporic acid)

  • GH SECRETION

    Inhibitory hypothalamic factors

    • Obesity

    •  - adrenergic stimulation

    • Glucocorticoid

    • High FFA

    • Hyperglycemia

    • Hypothyroidism

    • IGF -1

  • GH SECRETION

     Inhibitory peripheral factors

    • Under nutrition

    • Acute illness

    • Chronic illness

    • GH receptor (GHR) deficiency

    • GHR antibodies

    • IGF –1 receptor deficiency

  • Growth hormone

    • Fetal pituicytes secrete GH in vitro by 5

    weeks

    • GH secretion varies with chronological age

    – Neonatal period values of 25-35 microgram/l

    – Childhood period values of 5-7 microgram/l

    – Peaks again during puberty up to 12microgram/l

    – GH and IGF-1 begins to decline by late

    adolescence and continues to decline through

    out adult life

  • GH – IGF AXIS

    HYPOTHALAMUS

    PITUITARY

    GHRH

    GH

    Liver / bone /muscle

    Peripheral tissues

    Endocrine

    IGF -1

    Autocrine& paracrine

    IGF - 1

    GHR

  • IGF-1

    • IGF-1 is a basic peptide of 70 aminoacids

    • IGF-II is slightly acidic peptide of 67 amino acids

    • Both share 45-73 possible aminoacids position

    • Both have 50% amino acid homology to insulin

    • Like insulin, both have A&B chains connected by

    disulphide bonds

    • The connecting C-peptide region is 12 aminoacids

    long for IGF-1 and 8 aminoacids for IGF-II

  • Sm-C/ IGF-1

  • Actions of GH & IGF-1

    • GH effects are both direct and indirect

    • Indirect via IGF-1 production by liver

    • 99 % of hepatic IGF –1 in bound form

    • 75 – 90 % of circulating IGF-1 binds to IGFBP-3, remainder by IGFBP-1 & 2

    • GH stimulates production of IGF-1 from peripheral tissues (autocrine / paracrine effects)

  • IGFBP

     Six distinct but structurally related

    proteins

    • IGFBP- 1,2 &3 involved in binding to IGF 1

    • IGFBP-3, a glycoprotein is the major

    carrier for IGF-1

  • GROWTH HORMONE

    LIVER CARTILLAGE TISSUES

    Systemic

    IGF1

    Local

    IGF1

    Local

    IGF1

    Linear

    growth

    Linear

    growth

    Metabolic

    effects

  • Proliferative effects of IGF-1

  • Metabolic effects of GH

    • hGH has a well established effects on:

    – protein

    • Promote nitrogen retention and accrual of lean body

    mass

    – Carbohydrate

    • Increase hepatic glucose uptake

    – Lipid

    • Lipolytic, more for abdominal than S/C fat

    – Bone metabolism

    • Increase bone turnover with net gain in BMD

  • Metabolic effects of GH and IGF-1

    COMMENTSIGF-1GHEffects

    ------------------PROTEIN

    SYNTHESIS

    IGF-1 affects glucose

    metabolism via both

    insulin &IGF-1 receptor

    INSULIN

    SENSITIVITY

    IGF-1 acutely suppresses

    lipid oxidation, chronically

    increases it via insulin

    suppression

    LIPOLYSIS

    LIPID OXIDATION

    --------------------NO

    effect

    BONE DENSITY

  • The growth without growth hormone

    • The paradox of growth without GH has been recognized for over 30 years

    • The pathologic scenario in which this phenomena has most often been observed

    – following surgical resection of craniopharyngioma

    – Following surgical resection of suprasellar / hypothalamic tumours

    – Fetal life

    • Congenital GHD neonates have a normal length at birth

    – Obesity

    • Exact mechanism is unknown, but many possibilities

  • The growth without growth hormone

    • Proposed mechanisms

    – Obesity induced hyperinsulinemia

    – Hyperprolactinaemia

    – IGF-1 (autocrine or paracrine = non GH- dependent)

    – IGF-II

    – Other peptide growth factors

    • Fibroblast growth factor

    • Epidermal growth factor

    • Colony-stimulating factor

    • Other as yet unidentified serum growth factors

  • Growth Disorders

     Isolated GHD (Idiopathic / secondary)

     Pan Hypopituitarism

     GH insensitivity Disorders

     primary

     secondary

     IGF –1 receptor deficiency

  • Prevalence

    • Idiopathic Growth hormone deficiency

    affects 1/4000- 1/10,000 children

  • Isolated GH deficiency 1A

    • Autosomal Recessive

    • Onset starts in intrauterine life

    • Extreme short stature at adult life

    • Similar craniofacial features to other types

    • Strong early response to GH treatment

    • Early appearances of antibodies to GH

    • Complete deletion of GH 1 gene

  • Isolated GH deficiency 1B

    • Autosomal Recessive

    • Has low but detectable GH level

    • Good response to exogenous GH

    • No antibody formation after exogenous GH

    treatment

  • Isolated GH deficiency II &IIII

    Type II

    • Autosomal dominant

    • Decreased endogenous GH secretion

    • Good response to exogenous treatment with no antibodies formation

    Type III

    • X –linked Recessive

    • Some have X- linked agammaglobulinemia

    • Possible gene deletion coding both disorders (GH 1 gene is normal)

  • Familial Isolated GHD

    • IGHD IA AR Absent GH Severe

    • IGHD IB AR  GH

    • IGHD II AD  GH

    • IGHD III XLR  GH  hypogamma-

    globulinemia

    • IGHD IA is associated with antibodies

    development against GH therapy

  • Pan Hypopituiterism

    • Correlation between breech delivery and later

    development of pituitary hormone

    deficiencies.

    ? Primary or secondary

     Causes

    • Congenital

    • Inherited

    • Acquired

  • Pan Hypopituiterism

     Acquired causes  Tumors and their treatment

     Cranial irradiation

     Trauma

     Autoimmune “Lymphocytic Hypophysitis”

     Infiltrative ---- langer cell histeocytosis

     Metabolic --- iron overload

  • Pan Hypopituiterism

     Clinical presentations • Hypoglycemia

    • Hyperbilirubinemia

    • Micropenis

    • Growth failure > 2 y. (except, those with total GHD

    have intrauterine onset)

    • Optic atrophy & midline facial defect

    • Other hormonal deficiencies (DI,Pubertal

    disorders, hypothyroidism…..etc)

  • Pan Hypopituiterism

     Type I AR

     Type II XLR

    • Synthesis and release of GH is modulated by family of genes including transcription factors :

    Pit 1, Prop 1, Hesx 1 genes

  • Primary GH resistance

    Laron syndrome (LS)

     Hereditary / Congenital defects

    • GH Receptor (GHR) defects

    - quantitative

    - qualitative

    • GH - GHR signal transduction defects

    (post –receptor)

    • primary defects of IGF-1

    • GH - Inhibiting antibodies

  • Secondary GH resistance

     Acquired conditions

    • sometimes transient – may be partial • Antibodies to hGH that inhibit GH action (hGH gene

    deletion)

    • Antibodies to GHR

    • Malnutrition

    • Liver disease

    • Uncontrolled D